This invention relates to spiro-isoquinoline-pyrrolidine tetrones and their pharamaceutically acceptable salts thereof, to processes for their preparation, to methods for using the compounds, and to pharmaceutical preparations thereof. The compounds have pharmaceutical properties which render them beneficial for the prevention or treatment of complications associated with diabetes mellitus.
The use of insulin and/or oral hypoglycemic agents in the treatment of diabetes mellitus has prolonged the life of many of these patients. However, their use has not had a demonstrable impact on the development of diabetic complications such as neuropathy, nephropathy, retinopathy, cataracts and vascular disease which accompany the underlying metabolic disorder. There is little question that chronic hyperglycemia plays a major role in the genesis of these complications, and that complete normalization of blood glucose would likely prevent most if not all complications. For a number of reasons, though, chronic normalization of blood glucose has not been achieved with the currently available therapies. The development of diabetic complications has recently been linked to the increased accumulation of tissue sorbitol resulting from chronic hyperglycemia. Therapeutic reduction of sorbitol accumulation could potentially prevent the development of diabetic complications.
In mammals, including humans, the key enzyme involved in the conversion of glucose to sorbitol (e.g. the sorbitol pathway) is aldose reductase. J.H. Kinoshita and collaborators [see J.H. Kinoshita et al, Biochem. Biophys. Acta, 158, 472 (1968) and references cited therein] have demonstrated that this enzyme plays a central role in the etilogy of galactosemic cataracts by effecting the conversion of galactose to dulcitol (galactitol), and that an agent capable of inhibiting aldose reductase can prevent the detrimental accumulation of dulcitol in the lens. Furthermore, a relationship between elevated levels of glucose and an undesirable accumulation of sorbitol has been demonstrated in the lens, peripheral nerves and kidney of diabetic animals [see A. Pirie and R. van Heyningen, Exp. Eye Res., 3, 124 (1964); L.T. Chylack and J.H. Kinoshita, Invest. Ophthal., 8, 401 (1969) and J.D. Ward and R.W.R. Baker, Diabetol., 6, 531 (1970)].